1. Field of the Invention
The present invention relates to a solid dispersion composition containing 2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one (hereinafter referred to as xe2x80x9ccompound 1xe2x80x9d), which has excellent dissolvability and dissolution stability alike.
2. Background Art
Compound 1, which exerts an excellent effect for suppressing production of interleukin 1xcex2, is known to be useful as a prophylactic and therapeutic agent for immunological diseases, inflammatory diseases, and ischemic diseases, particularly as a therapeutic agent for articular rheumatism (disclosed in Japanese Patent Application Laid-Open (kokai) No. 2000-198776).
The present inventors have conducted studies on use of the aforementioned compound 1 in a peroral pharmaceutical composition. However, compound 1 has exceptionally poor solubility in water, and its dissolvability from the pharmaceutical composition is very bad. Thus, such a composition proved impossible to satisfy sufficient pharmaceutical effects.
Generally, dissolvability in water of a poor water dissoluble drug in a pharmaceutical composition is known to be improved by micro-pulverization of the drug and/or transformation of the drug into a derivative thereof. However, in the case of compound 1, micro-pulverization does not work; i.e., dissolvability is not improved, and transformation into a derivative results in unwanted changes in pharmaceutical effect.
Accordingly, the purpose of the present invention is to enhance the dissolvability of compound 1 from a pharmaceutical composition and thus provide the pharmaceutical composition containing said compound, which has the excellent dissolution stability with allowing said compound to keep a constant concentration after dissolving from the composition.
The present inventors have prepared compositions containing compound 1 and a variety of other components and investigated dissolvability of compound 1 contained in these compositions, and have found that, when a dispersion composition in solid form (hereinafter referred to as a solid dispersion composition) is prepared from compound 1, hydroxypropylmethyl cellulose, and polyoxyethylene polyoxypropylene glycol, dissolvability of compound 1 can be remarkably enhanced; that the concentration of compound 1 can be constant after dissolving from the composition; and that a composition useful as a peroral pharmaceutical can be obtained from the solid dispersion composition. The present invention has been accomplished on the basis of these findings.
Thus, the present invention provides a solid dispersion composition comprising compound 1, hydroxypropylmethyl cellulose, and polyoxyethylene polyoxypropylene glycol.
In another aspect of the present invention, there is provided a readily dissoluble pharmaceutical composition comprising a solid dispersion composition containing compound 1, hydroxypropylmethyl cellulose and polyoxyethylene polyoxypropylene glycol, and a pharmacologically acceptable carrier.
Compound 1 employed in the present invention; i.e., 2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one, can be produced through any known method, such as a method disclosed in Japanese Patent Application Laid-Open (kokai) No. 2000-198776.
Preferably, the solid dispersion composition of the present invention contains compound 1 in an amount of 0.1-35 wt. %, more preferably 1-30 wt. %, particularly preferably 5-25 wt. %.
The hydroxypropylmethyl cellulose which is employed in the present invention has a methoxy group content of 19-30 wt. %, preferably 28-30 wt. %, and a hydroxypropoxy group content of 4-12 wt. %, preferably 7-12 wt. %. More preferably, the hydroxypropylmethyl cellulose has a viscosity of 2.5-7 mm2/s (20xc2x0 C.). As used herein, viscosity is that measured at 20xc2x0 C. through a viscosity determination method 1 described in Japanese Pharmacopoeia (i.e., capillary tube viscometer method) by use of an aqueous solution in which a sample (2 g) is dissolved in water (98 mL). Specific examples include hydroxypropylmethyl cellulose 2208, hydroxypropylmethyl cellulose 2906, and hydroxypropylmethyl cellulose 2910; and, as commercial products, Metolose 90SH, Metolose 65SH, Metolose 60SH, TC-5E, TC-5R and TC-5S (product of Shin-Etsu Chemical Co., Ltd.); Metocel K, Metocel F, and Metocel E (product of Dow Chemical Co.); and Marpolose (product of Matsumoto Yushi-Seiyaku Co., Ltd.).
Preferably, hydroxypropylmethyl cellulose is incorporated in an amount of 2-15 parts by weight based on 1 part by weight of compound 1, particularly preferably 3-10 parts by weight.
Preferably, the polyoxyethylene polyoxypropylene glycol which is employed in the present invention has the mean degree of polymerization of ethylene oxide of 3-200, more preferably 54-196, particularly preferably 105-160, and the mean degree of polymerization of propylene oxide of 5-70, more preferably 5-40, particularly preferably 5-30.
Examples of polyoxyethylene polyoxypropylene glycol species include polyoxyethylene(105) polyoxypropylene(5) glycol, polyoxyethylene(120) polyoxypropylene(40) glycol, polyoxyethylene(160) polyoxypropylene(30) glycol, polyoxyethylene(196) polyoxypropylene(67) glycol, polyoxyethylene(20) polyoxypropylene(20) glycol, polyoxyethylene(200) polyoxypropylene(70) glycol, polyoxyethylene(3) polyoxypropylene(17) glycol, polyoxyethylene(42) polyoxypropylene(67) glycol, and polyoxyethylene(54) polyoxypropylene(39) glycol; and, as commercial products, PEP 101 (product of Freund Industrial Co., Ltd.); Adeka Pluronic F-87, Adeka Pluronic L-44, Adeka Pluronic F-68, and Adeka Pluronic L-31 (product of Asahi Denka Kogyo co., Ltd.); and Unilube, Unilube 40DP-40B, Unilube 70DP-950B, and Plonon (product of Nippon Oil and Fats Co., Ltd.). The parenthetic number refers to the mean degree of polymerization of ethylene oxide or propylene oxide.
Preferably, polyoxyethylene polyoxypropylene glycol is incorporated in an amount of 0.01-3 parts by weight based on 1 part by weight of compound 1, particularly preferably 0.1-1 parts by weight.
In a preferred mode, the three-component solid dispersion composition is produced by dissolving three components in a solvent and removing the solvent through the method as described hereinafter.
The solvent is selected on the solubility of these three components. Examples thereof include organic solvents such as methyl alcohol, ethyl alcohol, isopropyl alcohol, acetone, and dichloromethane; mixtures thereof; and mixtures thereof with water.
No particular limitation is imposed on the method of removing the solvent, and any method can be employed so long as the method enables removal of the solvent. Examples of the method include evaporation under reduced pressure; atomizing the solution by means of a spray dryer; and applying the solution to core particles (lactose, microcrystalline cellulose, anhydrous dibasic calcium phosphate, etc.) placed in an apparatus such as a fluid bed granulator or a rotary granulator, to thereby cause the solvent to be evaporated.
While the solid dispersion composition of the present invention is required to contain hydroxypropylmethyl cellulose and polyoxyethylene polyoxypropylene glycol, the effects of the present invention remain persistent even when other ingredients are added thereto.
From the standpoint of dissolvability of compound 1, the solid dispersion composition preferably has an average particle size of 1-1,000 xcexcm, more preferably 2-800 xcexcm, particularly preferably 10-600 xcexcm. As used herein, the average particle size refers to an average particle size as measured through a laser beam scattering diffraction method.
The readily-dissoluble pharmaceutical composition of the present invention may serve either as a solid dispersion composition which has beforehand been prepared to comprise comopound 1, hydroxypropylmethyl cellulose and polyoxyethylene polyoxypropylene glycol, or as a readily-dissoluble pharmaceutical composition mixed in various forms with a pharmacologically acceptable carrier. For the present invention, the latter composition is preferred from the viewpoint of dissolvability.
Examples of the pharmacologically acceptable carrier include excipients such as lactose, microcrystalline cellulose, sucrose, mannitol, light anhydrous silicic acid, and dibasic calcium phosphate; binders such as methyl cellulose, hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, and pullulan; disintegrants such as croscarmelose sodium, carmellose calcium, cros povidone and low-substituted hydroxypropyl cellulose; lubricants such as magnesium stearate and talc; colorants such as tar pigments and red ferric oxide; and flavoring agents such as stevia, aspartame, and perfume.
No particular limitation is imposed on the form of the dissolution-facilitating pharmaceutical composition of the present invention, and any form is acceptable so long as it is a solid form. Examples of forms for easy ingestion include tablets, capsules, granules, and fine granules.